A major impediment to the development of new, orally active therapeutic agents to treat many human diseases is the poor solubility of such agents in the aqueous environment of the intestinal tract. Cocrystals (stoichiometric molecular complexes of an active therapeutic agent complexed with a benign molecule) represent a potentially attractive and new approach that can be used to modify and tailor solubility and dissolution properties to enhance and [modulate] bioavailability. Cocrystalline solids have been shown to profoundly increase aqueous solubility. However, there remains a significant lack of understanding of the key physicochemical and biological factors that influence in vivo performance of cocrystals such as differential solubilization of cocrystal components by physiologically relevant surfactants, and differential absorption of the active ingredient and coformer. There is, therefore, a critical need to develop mechanistic-based strategies to guide cocrystal characterization, selection, and formulation leading to optimized oral delivery. Guided by strong preliminary data, the long-term goal is to develop novel and efficient strategies to enhance the oral delivery of water insoluble drugs based on the solid and solution chemistry control that cocrystals provide. The primary objective in this application is to establish the basi physicochemical principles that dictate cocrystal solubilization, dissolution and absorption, and to establish quantitative mathematical relationships that can be used to accurately predict cocrystal behavior in vitro and in vivo. The central hypothesis is that quantitative, science-based mathematical relationships [that represent the relevant physicochemical processes describing cocrystal, drug and coformer behavior] can be developed to predict cocrystal solubility and dissolution in physiologically relevant media, and application of this knowledge will allow accurate in vivo absorption and bioavailability predictions to be made. To test the central hypothesis and achieve the objectives of this project, three Specific Aims will be pursued: 1) identify key molecular and physicochemical parameters that predict cocrystal solubility in physiologically relevant media, 2) develop predictive diffusion/reaction models of cocrystal dissolution in physiologically relevant media and test in relevant in vitro dissolution systems, 3) assess the oral absorption mechanisms of cocrystal drugs in vitro and in vivo. This research is innovative because it represents a new and substantial departure from current research which focuses exclusively on the physical and chemical properties in the solid state and in simple aqueous solutions. This approach will be effective in integrating biologically relevant components such as surfactants with important oral absorption considerations of both the drug and the associated coformer that make up the cocrystal. This integrated physicochemical and biological model can be expected to lead to more effective and accurate predictions of cocrystal oral absorption rates and ultimately to the development of improved drug delivery systems to treat human diseases.